SUMMARY Pulmonary infections are a leading cause of sepsis/septicemia that poses substantial mortality and long- term morbidity and health care costs. Successful clearance of pathogens from the respiratory tract is dependent on effective innate immune responses. Understanding the innate immune mechanisms in the pulmonary system is critical for better immunotherapeutics or vaccines. The signaling cascades triggering innate immune responses consist of a delicate balance between pro-inflammatory signaling cascades, and counteracting anti-inflammatory signaling. However, it is not quite clear how these innate immune cascades converge to augment clear pathogens while reducing tissue damage. To explore the host defense cascades, we have focused on a primary gram-negative extracellular pathogen, Klebsiella pneumoniae since this bacterium induces severe lung infection followed by sepsis; multiple drug-resistant strains have recently emerged; and no effective vaccine is available. The proposal will use 4 specific aims to test the overall hypothesis: NLRP10 is a critical regulator of a host defense pathway through IL-17A that can be targeted for prevention or treatment. The first aim will explore if activation of NLRP10 augments bacterial clearance and neutrophil recruitment and function. The second aim will study if the NLRP10-dependent IL-17 production enhances host defense. The third aim will examine if NLRP10 disruption causes functional alterations in alveolar macrophages. The fourth aim will investigate if augmentation of NLRP10 signaling can enhance host defense against K. pneumoniae. We anticipate this proposal using a unique combination of in vivo and in vitro systems, including KO mice, overexpression, and adoptive transfer strategies will enhance our understanding of the mechanisms by which NLRP10 modulates pulmonary host defense in both physiologic and pathologic conditions.